Hydroxyalkyl and oxoalkyl substituted phenols as analgesics and sedatives

ABSTRACT

Compounds useful for pharmacological and medicinal purposes having the formulae ##STR1## wherein R is H, C 1  -C 5  alkanoyl; R 1  is H, benzyl, C 1  -C 5  alkanoyl, P(O)(OH) 2 , --CO(CH 2 ) 2  COOH or a basic acyl group; each of R 2  and R 4  is H, C 1  -C 6  alkyl, phenyl, pyridyl or (CH 2 ) y  C 6  H 5  ; y is 1-4; R 3  is H or CH 3  ; Z is C 1  -C 13  alkylene or --(alk 1 ) m  --O--(alk 2 ) n  --; each of (alk 1 ) and (alk 2 ) is C 1  -C 13  alkylene with the proviso that the summation of carbon atoms in (alk 1 ) plus (alk 2 ) is not greater than 13; each of m and n is 0 or 1; and W is H, pyridyl, phenyl, fluorophenyl or chlorophenyl; intermediates therefor and methods for their preparation and use.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain 2-(acyclic substituted)phenols andderivatives thereof having at the 5-position a --Z--W group wherein Z isalkylene having from one to thirteen carbon atoms or (alk₁)_(m)--O--(alk₂)_(n) -- wherein each of m and n is 0 or 1 and each of (alk₁)and (alk₂) is alkylene having from one to thirteen carbon atoms with theproviso that the summation of carbon atoms in (alk₁) plus (alk₂) is notgreater than thirteen; and W is hydrogen, phenyl, fluorophenyl,chlorophenyl or pyridyl; derivatives thereof, intermediates therefor andprocesses for their preparation. The products are useful as CNS agents,especially as analgesics, tranquilizers, sedatives and antianxietyagents in mammals, including man, and/or as anticonvulsants, diureticsand antidiarrheal agents in mammals, including man.

2. Description of the Prior Art

Despite the current availability of a number of analgesic agents, thesearch for new and improved agents continues, thus pointing to the lackof an agent useful for the control of broad levels of pain andaccompanied by a minimum of side-effects. The most commonly used agent,aspirin, is of no practical value for the control of severe pain and isknown to exhibit various undesirable side-effects. Other potentanalgesic agents such as d-propoxyphene, codeine, and morphine, possessaddictive liability. The need for improved and potent analgesic agentsis, therefore, evident.

More recently, great interest in cannabinol-type compounds as analgesicagents has been exhibited. (R. Mechoulam, Ed., "Marijuana. Chemistry,Pharmacology, Metabolism and Clinical Effects", Academic Press, NewYork, N.Y., 1973; Mechoulam, et al., Chemical Reviews, 76, 75-112[1976]).

SUMMARY OF THE INVENTION

It has now been found that certain 5-substituted phenols having at the2-position an acyclic ketone or alcohol group are effective as CNSagents, especially as analgesics, tranquilizers, sedatives andantianxiety agents in mammals, including man, and/or as anticonvulsants,diuretics and antidiarrheal agents in mammals, including man (formulae Iand II below). Also included in this invention are various derivativesof said compounds which are useful as dosage forms of the compunds,intermediates therefor and methods for their preparation. The compoundsand derivatives thereof have the formulae ##STR2## (in whichstereochemistry is not represented) wherein: R is selected from thegroup consisting of hydrogen and alkanoyl having from one to five carbonatoms;

R₁ is selected from the group consisting of hydrogen, benzyl, alkanoyl,having from one to five carbon atoms, --P(O)(OH)₂ and the mono- anddisodium and potassium salts thereof, --CO(CH₂)₂ --COOH and the sodiumand potassium salts thereof, and --CO--(CH₂)_(p) --NR₅ R₆ wherein p is 0or an integer from 1 to 4; each of R₅ and R₆ when taken individually isselected from the group consisting of hydrogen and alkyl having from oneto four carbon atoms; R₅ and R₆ when taken together with the nitrogen towhich they are attached form a 5- and 6-membered heterocyclic ringselected from the group consisting of piperidino, pyrrolo, pyrrolidino,morpholino and N-alkylpiperazino having from one to four carbon atoms inthe alkyl group;

each of R₂ and R₄ is selected from the group consisting of hydrogen,alkyl having from one to six carbon atoms, phenyl, pyridyl andphenylalkyl having from one to four carbon atoms in the alkyl moiety;

R₃ is selected from the group consisting of hydrogen and methyl;

Z is selected from the group consisting of (a) alkylene having from oneto thirteen carbon atoms; (b) --(alk₁)_(m) --O--(alk₂)_(n) -- whereineach of (alk₁) and (alk₂) is alkylene having from one to thirteen carbonatoms, with the proviso that the summation of carbon atoms in (alk₁)plus (alk₂) is not greater than thirteen; each of m and n is 0 or 1; and

W is selected from the group consisting of hydrogen, pyridyl, ##STR3##wherein W₁ is selected from the group consisting of hydrogen, fluoro andchloro.

Also included in this invention are the pharmaceutically acceptable acidaddition salts of those compounds of formulae I and II which contain abasic group. In compounds having two or more basic groups present, suchas those wherein the W variable is pyridyl and/or OR₁ represents a basicester moiety, polyacid addition salts are, of course, possible.Representative of such pharmaceutically acceptable acid addition saltsare the mineral acid salts such as the hydrochloride, hydrobromide,sulfate, phosphate, nitrate; organic acid salts such as the citrate,acetate, sulfosalicylate, tartrate, glycolate, malate, malonate,maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate,2-hydroxy-3-naphthoate, lactate, mandelate and methane sulfonate.

Compounds of formula II can exist in diastereomeric forms by virtue ofthe asymmetric center at which the OR group is attached. Additionally,compounds of formulae I and II may contain asymmetric centers in the4-position substituent (Z-W) of the phenyl ring.

For convenience, the above formulae depict the racemic compounds.However, the above formulae are considered to be generic to andembracive of the racemic modifications of the compounds of thisinvention, the diastereomeric mixtures, the pure enantiomers anddiastereomers thereof. The utility of the racemic mixture, thediastereomeric mixture as well as of the pure enantiomers anddiastereomers is determined by the biological evaluation proceduresdescribed below.

Compounds of formula I wherein R₁ is H exist, in solution, inequilibrium with their hemiketal forms. Spectral evidence indicates thehemiketal to be the predominant form. In the solid state, spectralevidence indicates the compounds exist substantially completely in thehemiketal form. The keto and hemiketal forms of compounds of formula Iare included in this invention.

Favored because of their greater biological activity relative to that ofother compounds described herein, are compounds of formulae I-II whereinR is hydrogen; R₂ is hydrogen or alkyl; R₁ is hydrogen or alkanoyl; R₃is hydrogen or methyl; and Z and W have the values shown below:

    ______________________________________                                          Z              m     n       W                                              ______________________________________                                        alkylene having from 5 to 10                                                                   --    --    H                                                carbon atoms                                                                  alkylene having from 2 to 6 carbon atoms                                                       --    --                                                                                   ##STR4##                                        (alk.sub.1).sub.mO(alk.sub.2).sub.n                                                            0     1                                                                                    ##STR5##                                        (alk.sub.1).sub.mO(alk.sub.2).sub.n                                                            1     0                                                                                    ##STR6##                                        ______________________________________                                    

Preferred compounds of formulae I-II, and especially of formula II, arethose preferred compounds wherein Z and W have the values shown:

    ______________________________________                                          Z                 W                                                         ______________________________________                                        C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                                H                                                         CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                          H                                                         OCH(CH.sub.3)(CH.sub.2).sub.3                                                                     C.sub.6 H.sub.5                                           CH(CH.sub.3)(CH.sub.2).sub.3                                                                      C.sub.6 H.sub.5                                           ______________________________________                                    

and each of R, R₁ and R₃ is hydrogen; and each of R₂ and R₄ is alkyl.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula I are prepared by conjugate addition of anappropriate 2-bromo-5-(Z-W substituted)phenol to an α,β-unsaturatedketone via the Grignard reaction. The process comprises, as first step,protection of the phenolic hydroxy group.

Suitable protecting groups are those which do not interfere withsubsequent reactions and which can be removed under conditions which donot cause undesired reactions at other sites of said compounds or ofproducts produced therefrom. Representative of such protective groupsare methyl, ethyl, benzyl or substituted benzyl wherein the substituentis, for example, alkyl having from one to four carbon atoms, halo (Cl,Br, F, I) and alkoxy having from one to four carbon atoms.

The exact chemical structure of the protecting group is not critical tothis invention since its importance resides in its ability to perform inthe manner described above. The selection and identification ofappropriate protecting groups can easily and readily be made by oneskilled in the art. The suitability and effectiveness of a group as ahydroxy protecting group are determined by employing such a group in theherein-illustrated reaction sequences. It should, therefore, be a groupwhich is easily removed to regenerate the hydroxy group. Methyl is afavored protecting group since it is easily removed by treatment withpyridine hydrochloride. The benzyl group, also a favored protectinggroup, is removed by catalytic hydrogenolysis or acid hydrolysis.

The protected 2-bromo-5-(Z-W substituted)phenol is then converted to thecorresponding Grignard reagent in known manner as, for example, byrefluxing a mixture of one molar proportion of the bromo reactant andtwo molar proportions of magnesium in a reaction-inert solvent, e.g.cyclic and acyclic ethers such as tetrahydrofuran, dioxane and dimethylether of ethylene glycol. The resulting mixture is then cooled to about0° C. to -20° C. and a cuprous salt (CuBr, CuCl or CuI) added followedby the appropriate α,β-unsaturated ketone. A cuprous salt is generallyadded to increase conjugate addition of the Grignard reagent to theα,β-unsaturated ketone. The amount of cuprous salt used is not criticalbut can vary widely. Molar proportions ranging from about 0.2 to about0.02 moles per mole of bromo reactant afford satisfactory yields ofconjugate addition product.

Appropriate α,β-unsaturated ketones are those of formula III below:##STR7## wherein R₂, R₃ and R₄ are as defined above.

Many of the α,β-unsaturated ketones of formula III are known compounds.Those that are not known are conveniently prepared via the reaction ofappropriate phosphonate carbanions with appropriate aldehydes or ketonesaccording to the Wadsworth-Emmons modification of the Wittig reaction(J. Am. Chem. Soc., 83, 1733-8, 1961). The reaction, in general,comprises treating a dialkylacylphosphonate with an aldehyde or ketonein an aprotic solvent, e.g. 1,2-dimethoxyethane, diglyme, at atemperature of from about room temperature to about 110° C.Additionally, Grieco et al., J. Am. Chem. Soc., 95, 3071-2 (1973)describe a procedure for preparing dimethyl(2-oxoalkyl)phosphonateswhich serve as valuable starting materials in the above-mentionedWadsworth-Emmons modification of the Wittig reaction. The dialkylacylphosphonates required for these procedures are prepared by theMichaelis-Arbuzov reaction (Kosolapoff, "Organophosphorous Compounds",1st Ed., J. Wiley and Sons, Inc., New York, N.Y., 1950, Chapter 7) whichcomprises reacting a trialkyl phosphite with an appropriate alkyl oraralkyl halide.

A convenient method for preparing compounds of this invention wherein--Z--W is --O--(alk₂)_(n) --W comprises the use of 4-bromo resorcinol asstarting material. The process comprises protecting the two hydroxygroups of the resorcinol by benzylation according to standardprocedures. The benzyl group is favored as protecting group in thismethod since it can easily be removed by catalytic hydrogenation withoutcleaving the ether group --O--(alk₂)_(n) --W. Other protecting groupssuch as alkyl (e.g., methyl or ethyl) can, of course, also be used.However, the benzyl protecting group is favored since it gives rise tofewer side reactions. The protected 4-bromo resorcinol is then subjectedto the Grignard reaction and reacted with the appropriateα,β-unsaturated ketone in a reaction-inert solvent in the mannerdescribed above. The (2,4-dibenzyloxyphenyl)alkanone thus produced isthen subjected to catalytic hydrogenation over palladium-on-carbon toproduce the corresponding (2,4-dihydroxyphenyl)alkanone which existsprincipally in the form of its hemiketal. The hemiketal is thenconverted to the corresponding C₁₋₄ alkyl, e.g., methyl, ketal byreaction with, for example a trialkyl orthoformate, such astrimethylorthoformate in a suitable solvent such as a C₁₋₄ alcohol,e.g., methanol, in the presence of concentrated sulfuric acid. Thethus-produced alkyl ketal is then alkylated with the appropriate alkylor aralkyl methane sulfonate or tosylate in the presence of anhydroussodium or potassium carbonate in a suitable reaction-inert solvent suchas N,N-dimethylformamide at a temperature of from about 75°-100° C. Thismethod has the advantage of permitting the use of simpler compoundsthroughout the entire sequence of reactions. The O-alkylated oraralkylated/ketal is then deketalized by reaction with, for example,hydrochloric acid, to produce the corresponding(2-hydroxy-4-[O-(alk₂)_(n) ]phenyl)alkanone which exists principally inthe form of its hemiketal.

The 2-bromo-5-(Z-W substituted) phenol reactants are prepared bybromination of the appropriate 3-(Z-W substituted) phenol according tostandard procedures as, for example, by treatment with bromine in carbontetrachloride at a temperature of from about 20°-30° C. The necessary3-(Z-W substituted) phenols, if not known compounds, are prepared byprocedures illustrated herein. A convenient method for preparing suchreactants wherein the Z moiety is alkylene or (alk₁)--O--(alk₂)_(n) --comprises the Wittig reaction on an appropriate aldehyde such as2-(3-hydroxyphenyl)-2-methyl propionaldehyde, the hydroxy group of whichis protected by benzyl ether formation. The said aldehyde is thentreated with the appropriate alkyltriphenylphosphonium bromide, thealkyl group of which extends the propionaldehyde group to the desiredlength. In a typical procedure, the aldehyde reactant is added to aslurry of dimsyl sodium and alkyl triphenylphosphonium bromide indimethyl sulfoxide at a temperature below 30° C., e.g. from about 10° to30° C. When reaction is complete, the alkene substituted protectedphenol is recovered by known methods. Hydrogenation of the alkene overpalladium-on-carbon then affords the desired 3-(Z-W substituted)phenol.Judicious choice of the starting (3-hydroxyphenyl)substituted aldehydeand alkyl triphenylphosphonium bromide reactants affords the required3-(Z-W-substituted) phenol reactants.

A further procedure for making 3-(Z-W substituted) phenols wherein Z isalkylene or (alk₁)--O--(alk₂)_(n) -- comprises the Wittig reaction on anappropriate phenolic aldehyde or ketone, e.g., 3-hydroxybenzaldehyde ora 3-(hydroxyphenyl)alkyl ketone, in which the phenolic hydroxy group isprotected as by conversion to the benzyl, methyl or ethyl ether. Bychoice of appropriate reactants, compounds having straight or branchedalkylene groups (Z) can be produced. When a ketone, e.g.,3-hydroxyacetophenone is used as reactant, compounds wherein Z has amethyl group on the carbon atom adjacent to the phenyl group areobtained.

Substitution of a methyl or ethyl group at other sites, e.g., theβ-carbon atom of the alkylene group, is achieved by choice of theappropriate carboalkoxy alkylidene triphenylphosphorane, e.g., (C₆ H₅)₃P═C(R')--COOC₂ H₅. The unsaturated ester thus produced is reduced to thecorresponding alcohol by reaction with lithium aluminum hydride,generally in the presence of a small amount of aluminum chloride.Alternatively, when the phenolic protecting group is other than benzyl(e.g. methyl), the alcohol is produced by catalytic reduction of theunsaturated ester using palladium-carbon, followed by treatment of theunsaturated ester thus produced with lithium aluminum hydride.Conversion of the alcohol thus produced to the corresponding tosylate ormesylate followed by alkylation of the tosylate or mesylate with analkali metal salt of the appropriate HO-(alk₂)-W reactant, and finallyremoval of the protecting group affords the desired resorcinol 3-(Z-Wsubstituted) phenol.

A variation of the above sequence comprises bromination of the alcoholrather than converting it to a tosylate or mesylate. Phosphoroustribromide is a convenient brominating agent. The bromo derivative isthen reacted with the appropriate HO-(alk₂)-W in the presence of asuitable base (Williamson reaction).

The bromo compounds also serve as valuable intermediates for increasingthe chain length of the alkylene moiety in the above sequence to givecompounds wherein Z is -alkylene-W. The process comprises treating thebromo derivative with triphenyl phosphine to produce the correspondingtriphenylphosphonium bromide. Reaction of the triphenylphosphoniumbromide with the appropriate aldehyde or ketone in the presence of abase such as sodium hydride or n-butyl lithium affords an unsaturatedderivative which is then catalytically hydrogenated to the correspondingsaturated compound.

An alternative method for introducing an alkyl or aralkyl group into thearomatic nucleus, and specifically such a group wherein the carbon atomadjacent the aromatic nucleus is a tertiary carbon atom, comprises acidcatalyzed electrophilic substitution of guaiacol with a tertiary alcoholin the presence of an acid. e.g. methane sulfonic acid. The generalprocedure consists in reacting a mixture of methanesulfonic acid andequimolar amounts of guaiacol and tertiary alcohol at temperatures offrom about 30° C. to about 80° C. until reaction is substantiallycomplete. The product is isolated by pouring the reaction mixture ontoice followed by extraction with a suitable solvent such as methylenechloride. The 2-methoxy-4-alkyl phenol is then converted to the desired3-alkyl phenol by removal of the phenolic hydroxy group. The processcomprises converting the hydroxy group to a dialkyl phosphate group byreaction with a dialkyl chlorophosphonate, e.g. diethylchlorophosphonate, or with diethyl phosphonate and triethylamine.Treatment of the dialkyl phosphate with lithium/ammonia followed bydemethylation of the resulting alkylated methyl ether with borontribromide or pyridine hydrochloride or other known demethylating agentsaffords the desired 3-alkylphenol.

Esters of compounds of formulae I and II wherein R₁ is alkanoyl or--CO--(CH₂)_(p) NR₄ R₅ are readily prepared by reacting formulae I andII compounds wherein R₁ is hydrogen with the appropriate alkanoic acidor acid of formula HOOC--(CH₂)_(p) --NR₄ R₅ in the presence of acondensing agent such as dicyclohexylcarbodiimide. Alternatively, theyare prepared by reaction of a formula I or II compound with theappropriate alkanoic acid chloride or anhydride, e.g., acetyl chlorideor acetic anhydride, in the presence of a base such as pyridine.

Phosphate esters are prepared by treating the appropriate compound offormula I or II with potassium hydride followed bydibenzylphosphorochloridate. Catalytic hydrogenation of thedibenzylphosphate ester affords the desired phosphate ester. Cautiousneutralization with sodium or potassium hydroxide provides thecorresponding sodium or potassium salts.

The analgesic properties of the compounds of this invention aredetermined by tests using nociceptive stimuli.

TESTS USING THERMAL NOCICEPTIVE STIMULI (a) Mouse Hot Plate AnalgesicTesting

The method used is modified after Woolfe and MacDonald, J. Pharmacol.Exp. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied tothe feet of mice on a 1/8-inch thick aluminum plate. A 250 wattreflector infrared heat lamp is placed under the bottom of the aluminumplate. A thermal regulator, connected to thermistors on the platesurface, programs the heat lamp to maintain a constant temperature of57° C. Each mouse is dropped into a glass cylinder (61/2-inch diameter)resting on the hot plate, and timing is begun when the animal's feettouch the plate. The mouse is observed at 0.5 and 2 hours aftertreatment with the test compound for the first "flicking" movements ofone or both hind feet, or until 10 seconds elapse without suchmovements. Morphine has an MPE₅₀ =4-5.6 mg./kg. (s.c.).

(b) Mouse Tail Flick Analgesic Testing

Tail flick testing in mice is modified after D'Amour and Smith, J.Pharmacol. Exp. Ther., 72, 74-79 (1941) using controlled high intensityheat applied to the tail. Each mouse is placed in a snug-fitting metalcylinder, with the tail protruding through one end. This cylinder isarranged so that the tail lies flat over a concealed heat lamp. At theonset of testing an aluminum flag over the lamp is drawn back, allowingthe light beam to pass through the slit and focus onto the end of thetail. A timer is simultaneously activated. The latency of a sudden flickof the tail is ascertained. Untreated mice usually react within 3-4seconds after exposure to the lamp. The end point for protection is 10seconds. Each mouse is tested at 0.5 and 2 hours after treatment withmorphine and the test compound. Morphine has an MPE₅₀ of 3.2-5.6 mg./kg.(s.c.).

(c) Tail Immersion Procedure

The method is a modification of the receptable procedure developed byBenbasset, et al., Arch. int. Pharmacodyn., 122 434 (1959). Male albinomice (19-21 g.) of the Charles River CD-1 strain are weighed and markedfor identification. Five animals are normally used in each drugtreatment group with each animal serving as its own control. For generalscreening purposes, new test agents are first administered at a dose of56 mg./kg. intraperitoneally or subcutaneously, delivered in a volume of10 ml./kg. Preceding drug treatment and at 0.5 and 2 hours post drug,each animal is placed in the cylinder. Each cylinder is provided withholes to allow for adequate ventilation and is closed by a round nylonplug through which the animal's tail protrudes. The cylinder is held inan upright position and the tail is completely immersed in the constanttemperature waterbath (56° C.). The endpoint for each trial is anenergetic jerk or twitch of the tail coupled with a motor response. Insome cases, the endpoint may be less vigorous post drug. To preventundue tissue damage, the trial is terminated and the tail removed fromthe waterbath within 10 seconds. The response latency is recorded inseconds to the nearest 0.5 second. A vehicle control and a standard ofknown potency are tested concurrently with screening candidates. If theactivity of a test agent has not returned to baseline values at the2-hour testing point, response latencies are determined at 4 and 6hours. A final measurement is made at 24 hours if activity is stillobserved at the end of the test day.

TEST USING CHEMICAL NOCICEPTIVE STIMULI Suppression ofPhenylbenzoquinone Irritant-Induced Writhing

Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously ororally with saline, morphine, codeine or the test compound. Twentyminutes (if treated subcutaneously) or fifty minutes (if treated orally)later, each group is treated with intraperitoneal injection ofphenylbenzoquinone, an irritant known to produce abdominal contractions.The mice are observed for 5 minutes for the presence or absence ofwrithing starting 5 minutes after the injection of the irritant. MPE₅₀'s of the drug pretreatments in blocking writhing are ascertained.

TESTS USING PRESSURE NOCICEPTIVE STIMULI Effect on the Haffner TailPinch Procedure

A modification of the procedure of Haffner, Experimentelle PrufungSchmerzstillender. Mittel Deutch Med. Wschr., 55, 731-732 (1929) is usedto ascertain the effects of the test compound on aggressive attackingresponses elicited by a stimulus pinching the tail. Male albino rats(50-60 g.) of the Charles River (Sprague-Dawley) CD strain are used.Prior to drug treatment, and again at 0.5, 1, 2 and 3 hours aftertreatment, a Johns Hopkins 2.5-inch "bulldog" clamp is clamped onto theroot of the rat's tail. The endpoint at each trial is clear attackingand biting behavior directed toward the offending stimulus, with thelatency for attack recorded in seconds. The clamp is removed in 30seconds if attacking has not yet occurred, and the latency of responseis recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.).

TESTS USING ELECTRICAL NOCICEPTIVE STIMULI The "Flinch-Jump" Test

A modification of the flinch-jump procedure of Tenen,Psychopharmacologia, 12, 278-285 (1968) is used for determining painthresholds. Male albino rats (175-200 g.) of the Charles River(Sprague-Dawley) CD strain are used. Prior to receiving the drug, thefeet of each rat are dipped into a 20% glycerol/saline solution. Theanimals are then placed in a chamber and presented with a series of1-second shocks to the feet which are delivered in increasing intensityat 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.78,1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal'sbehavior is rated for the presence of (a) flinch, (b) squeak and (c)jump or rapid forward movement at shock onset. Single upward series ofshock intensities are presented to each rat just prior to, and at 0.5,2, 4 and 24 hours subsequent to drug treatment.

Results of the above tests are recorded as percent maximum possibleeffect (%MPE). The %MPE of each group is statistically compared to the%MPE of the standard and the predrug control values. The %MPE iscalculated as follows: ##EQU1##

The compounds of the present invention are active analgesics via oraland parenteral administration and are conveniently administered incomposition form. Such compositions include a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice. For example, they can be administered in theform of tablets, pills, powders or granules containing such excipientsas starch, milk sugar, certain types of clay, etc. They can beadministered in capsules, in admixtures with the same or equivalentexcipients. They can also be administered in the form of oralsuspensions, solutions, emulsions, syrups and elixirs which may containflavoring and coloring agents. For oral administration of thetherapeutic agents of this invention, tablets or capsules containingfrom about 0.20 to about 250 mg. are suitable for most applications.

The physician will determine the dosage which will be most suitable foran individual patient and it will vary with the age, weight and responseof the particular patient and the route of administration. Generally,however, the initial analgesic dosage in adults may range from about 1.0to about 1500 mg. per day in single or divided doses. In many instances,it is not necessary to exceed 250 mg. daily. The favored oral dosagerange is from about 1.0 to about 300 mg./day; the preferred range isfrom about 1.0 to about 100 mg./day. The favored parenteral dose is fromabout 1.0 to about 100 mg./day; the preferred range from about 1.0 toabout 50 mg./day.

This invention also provides pharmaceutical compositions, including unitdosage forms, valuable for the use of the herein described compounds asanalgesics and other utilities disclosed herein. The dosage form can begiven in single or multiple doses, as previously noted, to achieve thedaily dosage effective for a particular utility.

The compounds (drugs) described herein can be formulated foradministration in solid or liquid form for oral or parenteraladministration. Capsules containing drugs of this invention are preparedby mixing one part by weight of drug with nine parts of excipient suchas starch or milk sugar and then loading the mixture into telescopinggelatin capsules such that each capsule containing 100 parts of themixture. Tablets containing said compounds are prepared by compoundingsuitable mixtures of drug and standard ingredients used in preparingtablets, such as starch, binders and lubricants, such that each tabletcontains from 0.20 to 250 mg. of drug per tablet.

Suspensions and solutions of these drugs are frequently prepared justprior to use in order to avoid problems of stability of the drug (e.g.oxidation) or of suspensions or solution (e.g. precipitation) of thedrug upon storage. Compositions suitable for such are generally drysolid compositions which are reconstituted for injectableadministration.

Their activity as diuretic agents is determined by the procedure ofLipschitz et al., J. Pharmacol., 197, 97 (1943) which utilizes rats asthe test animals. The dosage range for this use is the same as thatnoted above with respect to the use of the herein described compounds asanalgesic agents.

Antidiarrheal utility is determined by a modification of the procedureof Neimegeers et al., Modern Pharmacology-Toxicology, Willem van Beverand Harbans Lal, Eds., 7, 68-73 (1976). Charles River CD-1 rats (170-200gms) are housed in group cages 18 hours before testing. The animals arefasted overnight with water available ad libitum prior to administrationof castor oil. The test drug is administered subcutaneously or orally ata constant volume of 5 ml/kg. of body weight in a 5% ethanol, 5%Emulphor EL-620 (a polyoxyethylated vegetable oil emulsifying agentavailable from Antara Chemicals, New York, N.Y.), and 90% saline vehiclefollowed one hour later with a challenge of castor oil (one ml.,orally). The animals are placed in small individual cages (20.5×16×21cm.) having suspended wire floors. A disposable cardboard sheet isplaced beneath the wire floors and examined one hour after castor oilchallenge for the presence or absence of diarrhea. A vehicle/castor oiltreatment group serves as control for each day's testing. Results arerecorded as the number of animals protected at one hour post challenge.In general, the dosage levels for use of these compounds asantidiarrheal agents parallels those with respect to their use asanalgesic agents.

The tranquilizer activity of the compounds of this invention isdetermined by orally administering them to rats at doses of from about0.01 to about 50 mg./kg. of body weight and observing the subsequentdecreases in spontaneous motor activity. The daily dosage range inmammals is from about 0.01 to about 100 mg.

Anticonvulsant activity is determined by subcutaneously administeringthe test compound to male Swiss mice (Charles River) weighing 14-23 g.in a vehicle of the type used for antidiarrheal utility. The mice areused in groups of five. The day before use, the mice are fastedovernight but watered ad lib. Treatments are given at volumes of 10 ml.per kg. via a 25 gauge hypodermic needle. Subjects are treated with thetest compound and, one hour after challenge, electroconvulsive shock, 50mA. at 60 Hz. administered transcorneally. Controls are simultaneouslyrun in which the mice are given only the vehicle as control treatment.The electroconvulsive shock treatment produces tonic extensorconvulsions in all control mice with a latency of 1.5-3 seconds.Protection is recorded when a mouse exhibits no tonic extensorconvulsions for 10 seconds after administration of electroconvulsiveshock.

Antianxiety activity is determined in a manner similar to that forevaluating anticonvulsant activity except that the challenge convulsantis pentylenetetrazole, 120 mg./kg. administered intraperitoneally. Thistreatment produces clonic convulsions in less than one minute in over95% of control mice treated. Protection is recorded when the latency toconvulse is delayed at least 2-fold by a drug pretreatment.

Sedative/depressant activity is determined by treating groups of sixmice subcutaneously with various doses of test agents. At 30 and 60minutes post treatment, the mice are placed on a rotorod for one minuteand evaluated for their performance on the rotorod. Inability of themice to ride the rotorod is taken as evidence of sedative/depressantactivity.

EXAMPLE 1 4-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone

A solution of 3.89 g. (0.010 mol.) of1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene in 15 ml. oftetrahydrofuran is slowly added to 0.36 g. (0.015 mol.) of 70-80 meshmagnesium metal. The resultant mixture is refluxed for 20 minutes and isthen cooled to -10° C. Cuprous iodide (0.115 g., 0.006 mol.) is addedand stirring continued for 10 minutes. To the resultant mixture isslowly added a solution of 0.701 g. (0.010 mol.) of methyl vinyl ketonein 5 ml. of tetrahydrofuran at such a rate that the reaction temperaturecould be maintained below 0° C. The reaction mixture is stirred for 30minutes longer (t<0° C.) and is then added to 100 ml. of 1 Nhydrochloric acid and 100 g. of ice. The quenched reaction is extractedthree times with 150 ml. portions of ether. The combined ether extractis washed twice with 100 ml. portions of water, twice with 100 ml.portions of saturated sodium chloride, dried over magnesium sulfate andevaporated to an oil. The oil was purified via column chromatography on180 g. of silica gel eluted with 20% ether-cyclohexane to yield 1.07 g.(28%) of the title compound as an oil.

PMR δ_(CDCl).sbsb.3^(TMS) 0.80 (m, terminal sidechain methyl), 1.22 (s,gem dimethyl), 2.03 (s, CH₃ CO), 2.72 (m, two methylenes), 5.00 (s,benzyl ether methylene), 6.6-6.8 (m, ArH), 6.90 (d, J=8 Hz, ArH) and7.22 (bs, PhH).

The above procedure is repeated but using the appropriate alkenone asreactant in place of methyl vinyl ketone and the appropriate1-bromo-2-benzyloxy-4-(Z-W)benzene to prepare:

4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-pentanone as an oil (3.99g., 66%) from 1.26 g. (0.0154 mol.) of 3-penten-2-one and 6.0 g. (0.0154mol.) of 1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.81 (m, terminal sidechain methyl), 1.24 (s,gem dimethyl), 2.00 (s, CH₃ CO), 2.65 (m, OCCH₂), 3.2-4.0 (m, benzylicmethine), 5.07 (s, benzyl ether methylene), 6.85 (m, ArH), 7.07 (d, J=8Hz, ArH) and 7.34 (bs, PhH).

IR: (CHCl₃) 1715, 1613 and 1575 cm⁻¹.

MS: m/e 394 (M⁺), 337, 323 and 309.

EXAMPLE 2 4-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-2-butanone

A mixture of 0.5 g. (1.31 mmols.) of4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone, 360 mg. ofsolid sodium bicarbonate, 100 mg. of 10% palladium-on-carbon and 10 ml.of ethanol is stirred under one atmosphere of hydrogen pressure for onehour. The reaction mixture is filtered through diatomaceous earth withethyl acetate and the filtrate evaporated to an oil. The oil is purifiedvia column chromatography on 100 g. of silica gel eluted with 50%ether-cyclohexane to yield 247 mg. (93%) of the title compound as anoil.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.82 (m, terminal sidechain methyl), 1.22 (s,gem dimethyl), 1.60 and 2.15 (s, ratio 1:3, hemiketal and ketone forms),2.80 (bs, two methylenes) and 6.7-7.3 (m, ArH).

IR: (CHCl₃) 3636, 3571, 3289, 1706, 1623, 1603 and 1572 cm⁻¹.

MS: m/e 290 (M⁺), 275, 272, 257, 205 and 187.

By means of the above procedure, the following compound is prepared fromthe appropriate compound of Example 1.

4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanone (0.49 g., 35%)from 1.8 g. (4.60 mmols.) of4-[2-benzyloxy-4-1,1-dimethylheptyl)phenyl]-2-pentanone; M.P.79.5°-80.5° C. (from pentane).

PMR: δ_(CDCl).sbsb.3^(TMS) 0.84 (m, terminal sidechain methyl), 1.27 (s,gem dimethyl), 1.64 and 2.07 (s, hemiketal and methyl ketone methyls),6.75-7.25 (m, ArH).

IR: (CHCl₃) 3571, 3333, 1706 (w), 1623 and 1572 cm⁻¹.

MS: m/e 304 (M⁺), 289, 271, 247 and 219 cm⁻¹.

Analysis: Anal. Calc'd. for C₂₀ H₃₂ O₂ : C, 78.89; H, 10.59%. Found: C,79.06; H, 10.56%.

EXAMPLE 3 4-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanol

To a -15° C. solution of 0.5 g. (1.31 mmols.) of4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone (the product ofExample 1) in 5 ml. of methanol is added 50 mg. (1.31 mmols.) of sodiumborohydride. The reaction mixture is stirred for 30 minutes and is thenadded to 100 ml. of saturated sodium chloride-150 ml. ether. The etherextract is washed once with 100 ml. of saturated sodium chloride, driedover magnesium sulfate and evaporated to an oil. The oil is purified viacolumn chromatography on 100 g. of silica gel eluted with 1:1ether:cyclohexane to yield 419 mg. (84%) of the title compound as anoil.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.8 (m, terminal sidechain methyl), 1.10 (d,J=7 Hz, carbinol methyl), 1.23 (s, gem dimethyl), 2.6-2.9 (m, twomethylenes), 3.63 (sextet, carbinol methine), 5.00 (s, benzyl ethermethylene), 6.8-7.3 (m, ArH) and 7.30 (bs, PhH).

In like manner, the 2-pentanone compound of Example 1 is reduced togive:

4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-pentanol (273 mg., 15%)of diastereomer A and 825 mg. (45%) of diastereomer B, both as oils,from 1.8 g. (4.60 (mmols.) of4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-pentanone.

Diastereomer A:

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal sidechain methyl), 1.08 (d,J=6 Hz, methyl), 1.29 (s, gem dimethyl), 3.5 (m, carbinol and benzylicmethines), 5.09 (s, benzyl ether methylene), 7.0 (m, ArH) and 7.40 (bs,PhH).

IR: (CHCl₃) 3497, 1613 and 1572 cm⁻¹.

MS: m/e 396 (M⁺), 381, 311 and 91.

Diastereomer B:

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal sidechain methyl), 1.28 (s,gem dimethyl), 3.40 (m, methine), 3.80 (m, methine), 5.10 (s, benzylether methylene), 6.90 (m, ArH), 7.17 (d, J=8 Hz, ArH) and 7.42 (bs,PhH).

IR: (CHCl₃) 3546, 1616 and 1575 cm⁻¹.

MS: m/e 396 (M⁺), 381, 311 and 91.

EXAMPLE 4 4-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-2-butanol

A mixture of 390 mg. (1.02 mmols.) of4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanol, 360 mg. of solidsodium bicarbonate, 100 mg. of 10% palladium-on-carbon and 10 ml. ofethanol is stirred under one atmosphere of hydrogen for 20 minutes. Thereaction mixture is filtered through diatomaceous earth with ethylacetate and evaporated to an oil. The oil is purified via rapid columnchromatography on silica gel eluted with ether to give a quantitativeyield of the title compound as an oil.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal sidechain methyl), 1.25 (s,gem dimethyl), 1.62 (m, C-3 methylene), 2.6 (m, C-4 methylene), 3.9 (m,C-2 methine and two OH), 6.90 (dd, J=8 and 2 Hz, ArH), 6.86 (d, J=2 Hz,ArH) and 7.02 (d, J=8 Hz, ArH).

IR: (CHCl₃) 3597, 3300, 1629 and 1575 cm⁻¹.

MS: m/e 292 (M⁺), 274, 233, 207 and 189.

Similarly, the following compounds are prepared from correspondingbenzyl ethers:

4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol diastereomer A,(179 mg., 98%) from diastereomer A of4-[2-benzyloxy-4(1,1-dimethylheptyl)phenyl]-2-pentanol (236 mg., 0.595mmol.) as an oil.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal sidechain methyl), 1.28 (s,gem dimethyl), 3.50 (m, carbinol and benzylic methine), 6.82 (d, J=2 Hz,ArH), 6.84 (dd, J=8 and 2 Hz, ArH) and 7.16 (d, J=8 Hz, ArH).

IR: (CHCl₃) 3610, 3333, 1634 and 1577 cm⁻¹.

MS: m/e 306 (M⁺), 291, 288, 273, 221 and 203.

Anal. Calc'd. for C₂₀ H₃₄ O₂ : C, 78.38; H, 11.18%. Found: C, 78.26; H,11.07%.

4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol diastereomer B(quantitative yield) from 804 mg. (2.03 mmols.) of4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-pentanol diastereomer B,as an oil.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal sidechain methyl), 3.19(sextet, J=6 Hz, benzylic methine), 3.99 (sextet, J=6 Hz, carbinolmethine), 6.82 (d, J=2 Hz, ArH), 6.88 (dd, J=8 and 2 Hz, ArH) and 7.13(d, J=8 Hz, ArH).

IR: (CHCl₃) 3610, 3378, 1629 and 1575 cm⁻¹.

MS: m/e 306 (M⁺), 291, 288, 221 and 203.

EXAMPLE 5

The compounds tabulated below are prepared from appropriate2-bromo-5-(Z-W substituted)phenol benzyl ethers and α,β-unsaturatedreactants R₄ --CO--CH═CR₂ R₃ according to the procedures of Examples1-2. They exist principally in the hemiketal form.

    __________________________________________________________________________     ##STR8##                                                                      R.sub.4                                                                              R.sub.2                                                                              R.sub.3                                                                           Z           W                                              __________________________________________________________________________    n-C.sub.3 H.sub.7                                                                    H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               i-C.sub.3 H.sub.7                                                                    H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               t-C.sub.4 H.sub.9                                                                    H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               n-C.sub.6 H.sub.13                                                                   H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               C.sub.6 H.sub.5                                                                      H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               (CH.sub.2)C.sub.6 H.sub.5                                                            H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                     H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               C.sub.2 H.sub.5                                                                      CH.sub.3                                                                             H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               n-C.sub.4 H.sub.9                                                                    CH.sub.3                                                                             H  C(CH.sub.3).sub.2 (CH.sub. 2).sub.6                                                        H                                               C.sub.6 H.sub.5                                                                      CH.sub.3                                                                             H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                     CH.sub.3                                                                             H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                    H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             n-C.sub.6 H.sub.13                                                                   H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             C.sub.6 H.sub.5                                                                      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             C.sub.6 H.sub.5                                                                      CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               C.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                    H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             i-C.sub.3 H.sub.7                                                                    H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               C.sub.2 H.sub.5                                                                      i-C.sub.3 H.sub.7                                                                    H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.2 C.sub.6 H.sub.5                                                             n-C.sub.4 H.sub.9                                                                    H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.2 C.sub.6 H.sub.5                                                             C.sub. 2 H.sub.5                                                                     CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.2 C.sub.6 H.sub.5                                                             CH.sub.2 C.sub.6 H.sub.5                                                             H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.2 C.sub.6 H.sub.5                                                             C.sub.6 H.sub.5                                                                      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                     CH.sub.3                                                                             H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                     n-C.sub.6 H.sub.13                                                                   H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                     n-C.sub.4 H.sub.9                                                                    CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             H      CH.sub.3                                                                         CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                   H                                               CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                         (CH.sub.2).sub.5                                                                           H                                               n-C.sub.3 H.sub.7                                                                    H      CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.8                                                         H                                               CH.sub.3                                                                             H      CH.sub.3                                                                         (CH.sub.2).sub.13                                                                          H                                               n-C.sub.6 H.sub.13                                                                   H      CH.sub.3                                                                         (CH.sub.2).sub.13                                                                          H                                               i-C.sub.3 H.sub.7                                                                    H      CH.sub.3                                                                         (CH.sub.2).sub.9                                                                           H                                               C.sub.6 H.sub.5                                                                      CH.sub.3                                                                             CH.sub.3                                                                         (CH.sub.2).sub.11                                                                          H                                               (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                     H      CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                        H                                               CH.sub.3                                                                             H      CH.sub.3                                                                         CH(CH.sub.3)(CH.sub.2).sub.3                                                               C.sub.6 H.sub.5                                 CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                         CH(CH.sub.3)(CH.sub.2).sub.3                                                               4-FC.sub.6 H.sub.4                              sec-C.sub.4 H.sub.9                                                                  C.sub.2 H.sub.5                                                                      H  CH(CH.sub.3)(CH.sub.2).sub.4                                                               4-ClC.sub.6 H.sub.4 -C.sub.2 H.sub.5 n-C.sub                                  .5 H.sub.11 H (CH.sub.2).sub.9 C.sub.6                                        H.sub.5                                         C.sub.6 H.sub.5                                                                      CH.sub.3                                                                             H  CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                        4-ClC.sub.6 H.sub.4                             CH.sub.3                                                                             (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                     H  C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                        C.sub.6 H.sub.5                                 CH.sub.3                                                                             H      CH.sub.3                                                                         O(CH.sub.2).sub.4                                                                          C.sub.6 H.sub.5                                 i-C.sub.6 H.sub.13                                                                   H      CH.sub.3                                                                         OCH(CH.sub.3)(CH.sub.2).sub.3                                                              C.sub.6 H.sub.5                                 C.sub.6 H.sub.5                                                                      CH.sub.3                                                                             CH.sub.3                                                                         OCH(CH.sub.3)(CH.sub.2).sub.3                                                              C.sub.6 H.sub.5                                 (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                     C.sub.2 H.sub.5                                                                      H  O(CH.sub.2).sub.3                                                                          4-ClC.sub.6 H.sub.4                             CH.sub.3                                                                             C.sub.6 H.sub.5                                                                      H  O(CH.sub.2).sub.4                                                                          C.sub.6 H.sub.5                                 n-C.sub.6 H.sub.13                                                                   (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                     H  O(CH.sub.2).sub.4                                                                          C.sub.6 H.sub.5                                 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      H  O(CH.sub.2).sub.10                                                                         4-ClC.sub.6 H.sub.4                             CH.sub.2 C.sub.6 H.sub.5                                                             C.sub.6 H.sub.5                                                                      CH.sub.3                                                                         OCH(CH.sub.3)(CH.sub.2).sub.8                                                              C.sub.6 H.sub.5                                 CH.sub.3                                                                             (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                     H  OCH(CH.sub.3)(CH.sub.2).sub.10                                                             4-FC.sub.6 H.sub.4                              C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      H  O(CH.sub.2).sub.13                                                                         C.sub.6 H.sub.5                                 (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                     i-C.sub.6 H.sub.13                                                                   H  O(CH.sub.2).sub.4                                                                          C.sub.6 H.sub.5                                 CH.sub.3                                                                             CH.sub.3                                                                             H  (CH.sub.2).sub.3 O(CH.sub.2).sub.3                                                         H                                               n-C.sub.6 H.sub.13                                                                   CH.sub.3                                                                             H  (CH.sub.2).sub.4 OCH.sub.2                                                                 H                                               CH.sub.3                                                                             CH.sub.3                                                                             H  (CH.sub.2).sub.13 O                                                                        H                                               n-C.sub.3 H.sub.7                                                                    i-C.sub.3 H.sub.7                                                                    H  C(CH.sub.3).sub.2 (CH.sub.2).sub.2 O(CH.sub.2).sub.4                                       H                                               C.sub.6 H.sub.5                                                                      H      CH.sub.3                                                                         (CH.sub.2).sub.4 O                                                                         C.sub.6 H.sub.5                                 CH.sub.3                                                                             C.sub.6 H.sub.5                                                                      H  (CH.sub.2).sub.6 O(CH.sub.2).sub.7                                                         H                                               CH.sub.2 C.sub.6 H.sub.5                                                             (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                     H  CH(CH.sub.3)(CH.sub.2).sub.2 O                                                             C.sub.6 H.sub.5                                 n-C.sub.6 H.sub.13                                                                   H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               C.sub.6 H.sub.5                                                                      H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.7                                                         H                                               CH.sub.2 C.sub.6 H.sub.5                                                             H      H  CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                   H                                               (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                     H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               CH.sub.3                                                                             H      H  OCH(CH.sub.3)(CH.sub.2).sub.3                                                              C.sub.6 H.sub.5                                 t-C.sub.4 H.sub.9                                                                    H      H  O(CH.sub.2).sub.4                                                                          C.sub.6 H.sub.5                                 C.sub.6 H.sub.5                                                                      H      H  (CH.sub.2).sub.6 O                                                                         4-FC.sub.6 H.sub.4                              CH.sub.2 C.sub.6 H.sub.5                                                             H      H  (CH.sub.2).sub.13 O                                                                        4-FC.sub.6 H.sub.4                              (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                     H      H  (CH.sub.2).sub.6 O(CH.sub.2).sub.7                                                         C.sub.6 H.sub.5                                 i-C.sub.4 H.sub.9                                                                    H      H  CH O(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                    C.sub.6 H.sub.5                                 2-pyridyl                                                                            H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub. 6                                                        H                                               3-pyridyl                                                                            H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               4-pyridyl                                                                            H      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               4-pyridyl                                                                            H      CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               2-pyridyl                                                                            CH.sub.3                                                                             CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               4-pyridyl                                                                            n-C.sub.3 H.sub.7                                                                    H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               2-pyridyl                                                                            i-C.sub.6 H.sub.13                                                                   CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               4-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               3-pyridyl                                                                            C.sub.6 H.sub.5                                                                      H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               2-pyridyl                                                                            CH.sub.2 C.sub.6 H.sub.5                                                             CH.sub.3                                                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               4-pyridyl                                                                            (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                     H  C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                         H                                               4-pyridyl                                                                            4-pyridyl                                                                            H  O(CH.sub.2).sub.4                                                                          C.sub.6 H.sub.5                                 2-pyridyl                                                                            2-pyridyl                                                                            H  OCH(CH.sub.3)(CH.sub.2).sub.3                                                              C.sub.6 H.sub.5                                 __________________________________________________________________________

EXAMPLE 6

The compounds of Example 5 are reduced and debenzylated according to theprocedures of Examples 3 and 4 to produce diastereomeric compoundshaving the formula wherein R₂, R₃, R₄, Z and W are as defined in Example5: ##STR9##

EXAMPLE 7 4-[2-Acetoxy-4-(1,1-dimethylheptyl)phenyl-2-butanone

A solution of 2.0 g. of4-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]2-butanone in 15 ml. ofpyridine is treated at 10° C. with 10 ml. acetic anhydride and themixture stirred for 18 hours under nitrogen. It is then poured ontoice/water and acidified with dilute hydrochloric acid. The acidifiedmixture is extracted with ethyl acetate (2×100 ml.), the extractscombined, washed with brine and dried (MgSO₄). Evaporation under reducedpressure affords the title product as an oil.

Similarly, the remaining compounds of this invention of formulae I-IIare converted to their monoacetoxy esters (of the phenolic hydroxygroup) and by substitution of anhydrides of propionic, butyric andvaleric acid for acetic anhydride, to the corresponding esterderivatives.

EXAMPLE 8 2-Acetoxy-4-[2-acetoxy-4-(1,1-dimethylheptyl)phenyl]pentaneDiastereomer A

To a solution of 2.0 g. of4-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]2-pentanol diastereomer A in20 ml. of pyridine at 10° C. is added 20 ml. of acetic anhydride and themixture stirred under nitrogen for 18 hours. It is then poured ontoice/water and acidified with dilute hydrochloric acid. The product isisolated by extraction with ethyl acetate (2×100 ml.). The combinedextracts are washed with brine, dried (MgSO₄) and evaporated to give thediacetyl derivative as an oil.

In like manner, the compounds of formula I wherein R is hydrogen and R₁is hydrogen are converted to their diacyl derivatives. Replacement ofacetic anhydride by propionic, butyric or valeric acid anhydridesaffords the corresponding diacyl derivatives.

EXAMPLE 94-[2-(4-morpholinobutyryloxy)-4-(1,1-dimethylheptyl)phenyl]2-pentanone

Dicyclohexylcarbodiimide (0.227 g., 1.1 mmole) and 4-N-piperidylbutyricacid hydrochloride (0.222 g., 1.0 mmole) are added to a solution of4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanone (0.303 g., 1.0mmole) in methylene chloride (25 ml.) at room temperature. The mixtureis stirred for 18 hours and is then cooled to 0° C. and filtered.Evaporation of the filtrate affords the title product as itshydrochloride salt.

Similarly, the reactant of this example and the remaining phenoliccompounds of this invention are converted to the basic esters of thephenolic hydroxy group by reaction with the appropriate basic acidreagent. Esters wherein the R₁ moiety has the following values are thusprepared:

--COCH₂ NH₂

--CO(CH₂)₂ N(C₄ H₉)₂

--CO(CH₂)₂ -N-(methyl)piperazino

--COC(CH₃)₂ (CH₂)₂ -piperidino

--CO(CH₂)₃ N(C₂ H₅)₂

--COCH(CH₃)(CH₂)₂ -morpholino

--CO(CH₂)₃ -pyrrolo

--CO(CH₂)₃ -pyrrolidino

--COCH₂ -pyrrolo

--CO(CH₂)₃ -piperidino

--CO(CH₂)₄ NH₂

--CO(CH₂)₃ NH(C₃ H₇)

--CO(CH₂)₂ -N-butylpiperazino

Careful neutralization of the hydrochloride salts affords the free basicesters which are converted to other acid addition salts according to theprocedure of Example 10. In this manner, the hydrobromide, sulfate,acetate, malonate, citrate, glycolate, gluconate, succinate,sulfosalicylate and tartrate salts are prepared.

EXAMPLE 10 General Hydrochloride Salt Formation

Excess hydrogen chloride is passed into a solution of the appropriatecompound of formulae I-II having a pyridyl group and the resultingprecipitate separated and recrystallized from an appropriate solvent,e.g. methanol-ether (1:10).

The remaining compounds of formulae I-II which have a pyridyl group areconverted to their hydrochlorides in like manner.

Similarly, the hydrobromide, sulfate, nitrate, phosphate, acetate,butyrate, citrate, malonate, maleate, fumarate, malate, glycolate,gluconate, lactate, salicylate, sulfosalicylate, succinate, pamoate,tartrate and embonate salts are prepared.

EXAMPLE 11 4-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-2-butanol2'-O-Hemisuccinate Ester Sodium Salt

To a 0° C. solution of 1.00 g. (3.14 mmoles) of4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-butanol in 3 ml. ofdichloromethane is added 0.383 g. (3.14 mmoles) of4-N,N-dimethylaminopyridine. To the resultant solution is slowly added0.314 g. (3.14 mmoles) of succinic anhydride in one ml. ofdichloromethane. The reaction mixture is stirred for 4 hours at 0° C.and then 3.14 ml. of 1 N hydrochloric acid is slowly added. The reactionmixture is stirred 5 minutes longer and then added to 100 ml. water-100ml. dichloromethane. The dichloromethane extract is dried over magnesiumsulfate and evaporated. The residue is dissolved in 5 ml. of ethanol and3.14 ml. of 1 N sodium hydroxide in ethanol added. Addition of ethercauses crystallization. Recrystallization from ethanol-ether yields thetitle compound.

Replacement of sodium hydroxide by potassium hydroxide in the aboveprocedure affords the potassium salt.

By means of this procedure, the remaining compounds described herein areconverted to their hemisuccinate esters.

EXAMPLE 12 4-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-2-butanol2'-O-Phosphate Ester Monosodium Salt

To a 0° C. slurry of 0.126 g. (3.14 mmoles) of potassium hydride in 3ml. of dimethylformamide is added a solution of 1.00 g. (3.14 mmoles) of4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-butanol in 3 ml. ofdimethylformamide. After gas evolution ceases (˜10 min.) 0.932 g. (3.14mmoles) of dibenzylphosphorochloridate is slowly added. The reactionmixture is stirred for one hour and then added to 200 ml. ether-100 ml.water. The ether extract is washed with two 100 ml. portions of water,dried over magnesium sulfate and evaporated to a residue. The residue ismixed with 1.0 g. of 5% platinum on carbon and 25 ml. of ethanol andstirred under one atmosphere of hydrogen for 3 hours. The reactionmixture is filtered through diatomaceous earth and 3.14 ml. of 1 Nsodium hydroxide in ethanol slowly added to the filtrate. Addition ofether causes crystallization of the product. Recrystallization fromethanol then yields the title compound.

Similarly, the remaining compounds described herein are converted totheir phosphate ester monosodium salts and, by replacement of sodiumhydroxide with potassium hydroxide, to their corresponding potassiumsalts.

EXAMPLE 13

One hundred mg. of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-butanolare intimately mixed and ground with 900 mg. of starch. The mixture isthen loaded into telescoping gelatin capsules such that each capsulecontains 10 mg. of drug and 90 mg. of starch.

EXAMPLE 14

A tablet base is prepared by blending the ingredients listed below:

Sucrose--80.3 parts

Tapioca starch--13.2 parts

Magnesium stearate--6.5 parts

Sufficient trans-4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-butanoneis blended into this base to provide tablets containing 0.5, 1, 5, 10and 25 mg. of drug.

EXAMPLE 15

Suspensions of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanoneare prepared by adding sufficient amounts of drug to 0.5%methylcellulose to provide suspensions having 0.1, 0.5, 1, 5 and 10 mg.of drug per ml.

PREPARATION A 2-(3-Benzyloxyphenyl)-2-methylpropionitrile

To a solution of 1500 ml. of dimethylsulfoxide saturated with methylbromide is simultaneously added a solution of 294 g. (1.32 mole) of2-(3-benzyloxyphenyl)acetonitrile in 200 ml. dimethyl sulfoxide and asolution of 420 ml. of 50% aqueous sodium hydroxide. Methyl bromide iscontinuously bubbled through the reaction mixture during the aboveaddition (30 minutes) and then for 1.5 hours longer while the reactiontemperature is maintained at ≦50° C. with ice cooling. The reactionmixture is added to 2 liters of water 2 kg. ice and the resultantmixture extracted four times with 1 liter of ether. The combined etherextracts are washed twice with one liter of water, once with one literof saturated sodium chloride, dried over magnesium sulfate andevaporated to yield 325 g. (98%) of product as an oil.

PMR: δ_(CDCl).sbsb.3^(TMS) 1.70 (s, methyl), 5.12 (s, methylene),6.8-7.5 (m, ArH) and 7.45 (s, PhH).

IR: (CHCl₃) 2247, 1616 and 1603 cm⁻¹.

MS: m/e 251 (M⁺), 236, 160 and 91.

PREPARATION B 2-(3-Benzyloxyphenyl)-2-methylpropionaldehyde

To a 15° C. solution of 325 g. (1.25 mole) of2-(3-benzyloxyphenyl)-2-methylpropionitrile in 1.85 liters oftetrahydrofuran is added 1.6 moles of diisobutylaluminum hydride as a1.3 M solution in hexane (reaction temperature is maintained at 15°-18°C.). The reaction mixture is allowed to warm to room temperature and isstirred 2 hours longer. It is then quenched by addition to a solution of170 ml. of concentrated sulfuric acid in 670 ml. of water (temperature≦30° C.). The resultant mixture is allowed to warm to room temperatureand is then stirred an additional 2 hours. The organic layer isseparated and the aqueous phase extracted once with one liter of ether.The combined organic phase is washed with 500 ml. of water and 500 ml.of saturated sodium chloride, dried over magnesium sulfate andevaporated to yield 315 g. (99%) of the title product.

PMR: δ_(CDCl).sbsb.3^(TMS) 1.43 (s, methyls), 5.08 (s, methylenes),6.8-7.5 (m, ArH), 7.4 (s, PhH) and 9.55 (s, aldehyde).

PREPARATION C 2-(3-Benzyloxyphenyl)-2-methyl-cis-oct-3-ene

To a 15° C. solution of 1.8 moles of dimsyl sodium (from sodium hydrideand dimethyl sulfoxide) in 2 liters of dimethyl sulfoxide is added,portionwise, 768 g. (1.8 moles) of pentyltriphenylphosphonium bromide.The resultant slurry is stirred 15 minutes at 15°-20° C. and then 315 g.(1.24 moles) of 2-(3-benzyloxyphenyl)-2-methylpropionaldehyde is slowlyadded (reaction temperature ≦30° C.). The resultant mixture is stirredfor 4 hours at room temperature and is then added to 6 liters of icewater. The quenched reaction is extracted four times with one literportions of 50% ether-pentane. The combined extract is washed twice withone liter of water and once with one liter of saturated sodium chlorideand is then dried over magnesium sulfate and evaporated to yield an oil.Crystallization of this oil in 50% ether-pentane (to removetriphenylphosphine oxide), filtration and evaporation of the filtrategives 559 g. of oil. The crude oil is purified via column chromatographyon 2 kg. of silica gel eluted with 20% hexane-dichloromethane to yield217 g. (57%) of 2-(3-benzyloxyphenyl)-2-methyl-cis-oct-3-ene.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.75 (bt, J=6 Hz, terminal methyl), 1.1 (m,two sidechain methylenes), 1.43 (s, gem dimethyl), 1.60 (m, allylicmethylene), 5.09 (s, benzylic methylene), 5.28 (dt, J=12 and 6 Hz, vinylH), 5.70 (dd, J=12 and 1 Hz, vinyl H), 6.7-7.5 (m, ArH) and 7.42 (s,PhH).

IR: (CHCl₃) 1610 and 1587 cm⁻¹.

MS: m/e 308 (M⁺), 293, 274, 265, 251, 239, 225, 217 and 91.

Similarly, 1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene (13.5 g., 70%)is prepared from 15.75 g. (0.062 mol.) of2-(3-benzyloxyphenyl)-2-methylpropionaldehyde and 37.5 g. (0.0899 mol.)of hexyltriphenylphosphonium bromide. The product is an oil.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.78 (m, terminal sidechain methyl), 1.40 (s,gem dimethyl), 4.97 (s, benzyl ether methylene), 5.23 (m, vinyl H), 5.57(d, J=11 Hz, vinyl H) and 6.6-7.4 (m, ArH and PhH).

IR: (CHCl₃) 1608 and 1582 cm⁻¹.

MS: m/e 322 (M⁺), 307, 279, 274, 265 and 231.

PREPARATION D 2-(3-Hydroxyphenyl)-2-methyloctane

A mixture of 65 g. (0.211 mole) of2-(3-benzyloxyphenyl)-2-methyl-cis-oct-3-ene and 7.5 g. of 10%palladium-on-carbon in 100 ml. of ethanol is hydrogenated for one houron a Parr apparatus at 50 p.s.i. hydrogen pressure. Additional 7.5 g.portions of 10% palladium-on-carbon are added after one and two hours ofreaction and the reaction continued for 12 more hours. The reactionmixture is filtered through diatomaceous earth with ethanol and thefiltrate evaporated to an oil. The oil is purified via columnchromatography on one kg. of silica gel eluted with 50%hexane-dichloromethane to yield 105 g. (78%) of2-(3-hydroxyphenyl)-2-methyloctane.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (bt, terminal methyl), 1-1.9 (m,methylenes), 1.29 (s, gem dimethyl), 4.98 (s, phenol H) and 6.6-7.4 (m,ArH).

IR: (CHCl₃) 3571, 3311 and 1592 cm⁻¹.

MS: m/e 220 (M⁺), 205 and 135.

In like manner, 2-(3-hydroxyphenyl)-2-methylnonane is prepared in 82%(7.8 g.) yield from 13.0 g. (0.0406 mol.) of1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene. It is obtained as an oilhaving the characteristics:

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (m, terminal methyl), 1.27 (s, gemdimethyl), 5.25 (bs, OH) and 6.6-7.4 (m, ArH).

IR: (CHCl₃) 3571, 3279, 1563 and 1527 cm⁻¹.

MS: m/e 234 (M⁺), 219, 191, 178, 164, 149, 135 and 121.

PREPARATION E 2-(4-Bromo-3-hydroxyphenyl)-2-methyloctane

To a 0° C. solution of 110 g. (0.50 mole) of2-(3-hydroxyphenyl)-2-methyloctane in 200 ml. of carbon tetrachloride isadded dropwise a solution of 80 g. (0.50 mole) of bromine in 90 ml. ofcarbon tetrachloride (reaction temperature ≦30° C. with cooling). Thereaction mixture is stirred an additional 15 minutes and is thenevaporated to yield 150 g. (100%) of2-(4-bromo-3-hydroxyphenyl)-2-methyloctane.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (bt, terminal methyl), 0.8-1.9 (m,methylenes), 1.28 (s, gem dimethyl), 5.4 (bs, phenolic H), 6.78 (dd, J=8and 2 Hz, C-6 ArH), 7.02 (d, J=2 Hz, C-2 ArH) and 7.37 (d, J=8 Hz, C-5ArH).

In like manner, 2-(4-bromo-3-hydroxyphenyl)-2-methylnonane is preparedin 82% (8.5 g.) yield as an oil from 7.8 g. (0.033 mol.) of2-(3-hydroxyphenyl)-2-methylnonane:

PMR: δ_(CDCl).sbsb.3^(TMS) 0.86 (m, terminal methyl), 1.27 (s, gemdimethyl), 5.50 (bs, OH), 6.83 (dd, J=8 and 2 Hz, ArH), 7.08 (d, J=2 Hz,ArH) and 7.43 (d, J=8 Hz, ArH).

IR: (CHCl₃) 3279, 1613, and 1587 cm⁻¹.

MS: m/e 314, 312 (M⁺), 212, 210, 185 and 187.

PREPARATION F 2-(3-Benzyloxy-4-bromophenyl)-2-methyloctane

To a -18° C. slurry of 23.0 g. (0.575 mole) of potassium hydride in 400ml. of N,N-dimethylformamide is added over a 45 minute period a solutionof 150 g. (0.5 mole) of 2-(4-bromo-3-hydroxyphenyl)-2-methyloctane in400 ml. of N,N-dimethylformamide (reaction temperature ≦-15° C.). Thereaction mixture is stirred 15 minutes longer after which a solution of98.3 g. (0.575 mole) of benzyl bromide in 200 ml. ofN,N-dimethylformamide is added. The mixture is then warmed to roomtemperature and stirred 30 minutes longer. It is quenched by addition to6 liters of ice water. The quenched mixture is extracted six times with500 ml. of ether. The combined extract is washed twice with one literportions of water and once with one liter of saturated sodium chloride,dried over magnesium sulfate and evaporated to a quantitative yield ofthe title product.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.85 (bt, terminal methyl), 0.8-2.0 (m,methylenes), 1.22 (s, gem dimethyl), 5.17 (s, benzylic methylene) and6.7-7.6 (two multiplets, ArH and PhH).

IR: (CHCl₃) 1592 and 1575 cm⁻¹.

MS: m/e 390, 388 (M⁺), 375, 373, 354, 352, 305, 303 and 91.

And, 2-(3-benzyloxy-4-bromophenyl-2-methylnonane is prepared in 95%(10.4 g.) yield from 2-(3-hydroxy-4-bromophenyl)-2-methylnonane (8.5 g.,0.027 mol.), sodium hydride (0.744 g., 0.031 mol.) and benzyl bromide(5.3 g., 0.031 mol.) as an oil.

PMR: δ_(CDCl).sbsb.3^(TMS) 0.87 (terminal methyl), 1.23 (s, gemdimethyl), 5.18 (s, benzyl ether methylene), 6.8 (dd, J=8 and 2 Hz,ArH), 6.97 (d, J=2 Hz, ArH) and 7.43 (m, ArH and PhH).

IR: (CHCl₃) 1600 and 1575 cm⁻¹.

MS: m/e 404, 402 (M⁺), 305, 301, 91.

The compounds tabulated below are prepared according to the proceduresof Preparations C-F from appropriate reactants:

    ______________________________________                                         ##STR10##                                                                    Z                     W                                                       ______________________________________                                        C(CH.sub.3).sub.2 (CH.sub.2).sub.2                                                                  H                                                       C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                                 H                                                       C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                                  C.sub.6 H.sub.5                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                                  4-pyridyl                                               C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                                                  2-pyridyl                                               C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                                 C.sub.6 H.sub.5                                         CH(CH.sub.3)(CH.sub.2).sub.2                                                                        C.sub.6 H.sub.5                                         CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                                 4-ClC.sub.6 H.sub.4                                     CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                                 4-FC.sub.6 H.sub.4                                      (CH.sub.2).sub.5      H                                                       (CH.sub.2).sub.11     H                                                       (CH.sub.2).sub.13     H                                                       (CH.sub.2).sub.4      C.sub.6 H.sub.5                                         (CH.sub.2).sub.8      H                                                       ______________________________________                                    

PREPARATION G 3-Benzyloxy-4-bromophenol

To a 0° C. slurry of 1.7 g. (42.5 mmoles) of potassium hydride in 35 ml.of N,N-dimethylformamide is slowly added a solution of 7.22 g. (38.2mmoles) of 4-bromoresorcinol. The resultant mixture is stirred for 30minutes and then 4.54 ml. (38.2 mmoles) of benzyl bromide is slowlyadded. The reaction mixture is stirred 3 hours longer at 0° C. and thenadded to 200 ml. of cold water and 200 ml. of ether. The ether extractis washed twice with 200 ml. portions of water, dried over magnesiumsulfate and evaporated to an oil. The crude oil is purified via columnchromatography on 400 g. of silica gel eluted with 25% ether-pentane toyield (in order of elution) 2.2 g. (16%) of 2,4-dibenzyloxybromobenzene,0.21 g. (2%) of 5-benzyloxy-2-bromophenol and 3.52 g. (33%) of3-benzyloxy-4-bromophenol.

5-Benzyloxy-2-bromophenol:

PMR: δ_(CDCl).sbsb.3^(TMS) 4.98 (s, benzyl ether), 5.46 (bs, OH), 6.40(dd, J=8 and 2 Hz, ArH), 6.60 (d, J=2 Hz, ArH), 7.17 (d, J=8 Hz, ArH)and 7.33 (s, PhH).

IR: (CHCl₃) 3521, 3221, 1610 and 1600 cm⁻¹.

MS: m/e 280, 278 (M⁺), 189, 187 and 91.

3-Benzyloxy-4-bromophenol:

PMR: δ_(CDCl).sbsb.3^(TMS) 5.00 (s, benzyl ether methylene), 5.33 (bs,OH), 6.21 (dd, J=8 and 2 Hz, ArH), 6.38 (d, J=2 Hz, ArH) and 7.30 (m,ArH and PhH).

IR: (CHCl₃) 3546, 3257, 1603 and 1585 cm⁻¹.

MS: m/e 280, 278 (M⁺) and 91.

PREPARATION H 2-Benzyloxy-4-[2-(5-phenylpentyloxy)]bromobenzene

A mixture of 3.50 g. (12.5 mmoles) of 3-benzyloxy-4-bromophenol, 3.48 g.(14.4 mmoles) of 2-(5-phenylpentyl)methanesulfonate and 5.17 g. (37.5mmoles) of anhydrous potassium carbonate in 20 ml. ofN,N-dimethylformamide is heated at 85° C. for 6 hours. It is then cooledand added to 200 ml. of water and 200 ml. of ether. The organic extractis washed twice with 150 ml. portions of water, dried over magnesiumsulfate and evaporated to an oil. The oil is purified via columnchromatography on 400 g. of silica gel eluted with 2:1 pentane:methylenechloride to yield 4.39 g. (82%) of the desired product as an oil.

PMR: δ_(CDCl).sbsb.3^(TMS) 1.21 (d, J=6 Hz, sidechain methyl), 1.7 (m,sidechain methylenes), 2.60 (m, sidechain benzyl methylene), 4.25 (m,sidechain methine), 5.00 (s, benzyl ether methylene), 6.22 (dd, J=8 and2 Hz, C-5 ArH), 6.39 (d, J=2 Hz, C-3 ArH) and 7.30 (m, PhH and C-6 ArH).

IR: (CHCl₃) 1587 cm⁻¹.

MS: 426, 424 (M⁺), 280, 278 and 91.

The following compounds are similarly prepared from the appropriatemesylate CH₃ SO₃ -Z-W.

    ______________________________________                                         ##STR11##                                                                    (alk.sub.2)            W                                                      ______________________________________                                        (CH.sub.2).sub.4       4-FC.sub.6 H.sub.4                                     (CH.sub.2).sub.8       C.sub.6 H.sub.5                                        (CH.sub.2).sub.10      4-ClC.sub.6 H.sub.4                                    CH(CH.sub.3)(CH.sub.2).sub.8                                                                         C.sub.6 H.sub.5                                        CH(CH.sub.3)CH.sub.2   4-FC.sub.6 H.sub.4                                     C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                                                   C.sub.6 H.sub.5                                        CH.sub.2 CH(CH.sub.3)CH.sub.2                                                                        C.sub.6 H.sub.5                                        CH(CH.sub.3)(CH.sub.2).sub.10                                                                        H                                                      C(CH.sub.3).sub.2 (CH.sub.2).sub.5                                                                   H                                                      C(CH.sub.3).sub.2 (CH.sub.2).sub.7                                                                   H                                                      (CH.sub.2).sub.13      H                                                      (CH.sub.2).sub.13      C.sub.6 H.sub.5                                        CH(CH.sub.3)(CH.sub.2).sub.6                                                                         4-FC.sub.6 H.sub.4                                     C(CH.sub.3).sub.2 (CH.sub.2).sub.10                                                                  4-FC.sub.6 H.sub.4                                     (CH.sub.2).sub.12      C.sub.6 H.sub.5                                        CH(C.sub.2 H.sub.5)(CH.sub.2).sub.3                                                                  4-ClC.sub.6 H.sub.4                                    C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                                   H                                                      (CH.sub.2).sub.2 C(CH.sub.3 ).sub.2 (CH.sub.2).sub.2                                                 H                                                      (CH.sub.2).sub.6       C.sub.6 H.sub.5                                        (CH.sub.2).sub.12      H                                                      CH(CH.sub.3)(CH.sub.2).sub.3                                                                         4-pyridyl                                              (CH.sub.2).sub.2       4-pyridyl                                              CH(CH.sub.3)(CH.sub.2).sub.3                                                                         2-pyridyl                                              (CH.sub.2).sub.5       3-pyridyl                                              (CH.sub.2).sub.10      2-pyridyl                                              CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                                  4-pyridyl                                              ______________________________________                                    

PREPARATION I 1-Bromo-2,4-dibenzyloxybenzene

A mixture of 75.0 g. (0.397 mol.) of 4-bromoresorcinol, 95.1 ml. (0.80mol.) of benzylbromide and 331 g. (2.4 mol.) of anhydrous potassiumcarbonate in 400 ml. of N,N-dimethylformamide is stirred for 12 hours at25° C. and for 4 hour at 85° C. The reaction mixture is cooled and addedto one liter of ice-200 ml. pentane-100 ml. ether. The organic phase iswashed with three 500 ml. portions of water, dried over magnesiumsulfate and evaporated to an oil. The oil is rapidly chromatographed on400 g. of silica gel eluted with 20% ether-pentane to yield 80 g. ofoil. The chromatographed oil is crystallized from pentane at 0° C. toyield 45.0 g. (30%) of the title compound, M.P. 37°-38° C.

PMR: δ_(CDCl).sbsb.3^(TMS) 5.0 (s, C-4 benzylether methylene), 5.08 (s,C-2 benzylether methylene), 6.45 (dd, J=8 and 2 Hz, C-5H), 6.63 (d, J=2Hz, C-3H), 7.2-7.6 (m, PhH and ArH).

IR: (CHCl₃) 1605 and 1590 cm⁻¹.

MS: m/e 370 (M⁺), 368 and 91.

Analysis: Anal. Calc'd. for C₂₀ H₁₇ BrO₂ : C, 65.03; H, 4.64; Br, 21.65.Found: C, 64.95; H, 4.55; Br, 21.48.

PREPARATION J 2-(3-Methoxyphenyl)-5-phenylpentane

A solution of 1-bromopropylbenzene (51.7 g.) in ether (234 ml.) is addeddropwise over a 2-hour period to a refluxing mixture of magnesium (7.32g.) in ether (78 ml.). The reaction mixture is refluxed for 30 minuteslonger and then a solution of 3-methoxy-acetophenone (41.6 g.) in ether(78 ml.) is added dropwise and the mixture heated to reflux for 1.5hours. The reaction is quenched by addition of saturated ammoniumchloride (234 ml.), the ether layer is separated and the aqueous phaseextracted with ether (3×200 ml.). The combined ether extracts are driedover magnesium sulfate and concentrated under vacuum to yield an oil.The oil is hydrogenated in a mixture containing ethanol (300 ml.),concentrated hydrochloric acid (2 ml.) and 5% palladium-on-carbon (5g.). The catalyst is filtered off and the ethanol removed under vacuum.The residue is distilled under vacuum to give the title product.

PREPARATION K 2-(3-Hydroxyphenyl)-5-phenylpentane

A mixture of 2-(3-methoxyphenyl)-5-phenylpentane (18.4 g.) and pyridinehydrochloride (94 g.) under nitrogen is heated to 190° C. for 2 hourswith vigorous stirring. The reaction mixture is cooled, dissolved in 6 Nhydrochloric acid (200 ml.) and diluted with water to 600 ml. Theaqueous solution is extracted with ethyl acetate (4×100 ml.), the ethylacetate extracts dried over sodium sulfate and concentrated under vacuumto yield the crude product. The product is purified by silica gelchromatography.

The following compounds are prepared from appropriate reactants by themethod of Preparation J and that of the above preparation:

    ______________________________________                                         ##STR12##                                                                    Z                     W                                                       ______________________________________                                        CH(CH.sub.3)(CH.sub.2).sub.2                                                                        C.sub.6 H.sub.5                                         CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                                 4-ClC.sub.6 H.sub.4                                     CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                                 4-FC.sub.6 H.sub.4                                      (CH.sub.2).sub.5      H                                                       (CH.sub.2).sub.11     H                                                       (CH.sub.2).sub.13     H                                                       (CH.sub.2).sub.4      C.sub.6 H.sub.5                                         (CH.sub.2).sub.8      H                                                       ______________________________________                                    

Bromination of the above compounds according to the procedure ofPreparation E affords the corresponding 4-bromo derivatives, e.g.2-(4-bromo-3-hydroxyphenyl)-5-phenylpentane.

PREPARATION L Ethyl 3-(3-Benzyloxyphenyl)crotonate (Wittig Reaction)

A mixture of 3-benzyloxyacetophenone (29.4 g., 0.13 mole) andcarbethoxymethylenetriphenylphosphorane (90.5 g., 0.26 mole) is heatedunder a nitrogen atmosphere at 170° C. for 4 hours. The clear melt iscooled to room temperature, triturated with ether and the precipitate oftriphenyl phosphine oxide removed by filtration. The filtrate isconcentrated under vacuum to an oily residue which is chromatographedover silica gel (1500 g.) and eluted with benzene:hexane solutions ofincreasing benzene concentration beginning with 40:60 and ending with100% benzene. Concentration of appropriate fractions gives the productas an oily residue.

PREPARATION M 3-(3-Benzyloxyphenyl)butyl Tosylate

A solution of ethyl 3-(3-benzyloxyphenyl)crotonate (17.8 g., 60 mmole)in ether (250 ml.) is added to a mixture of lithium aluminum hydride(3.42 g., 90 mmole) and ether (250 ml.). Aluminum chloride (0.18 g.,1.35 mmole) is added and the mixture refluxed for 12 hours and thencooled. Water (3.4 ml.), sodium hydroxide (3.4 ml. of 6 N) and water (10ml.) are then added successively to the reaction mixture. The inorganicsalts which precipitate are filtered off and the filtrate is thenconcentrated in vacuo to give the 3-(3-benzyloxyphenyl)butanol as anoil.

Tosyl chloride (11.1 g., 58.1 mmole) is added to a solution of3-(3-benzyloxyphenyl)-1-butanol (14.5 g., 57 mmole) in pyridine (90 ml.)at -45° C. The reaction mixture is held at -35° C. for 18 hours and isthen diluted with cold 2 N hydrochloric acid (1500 ml.) and extractedwith ether (5×200 ml.). The combined extracts are washed with saturatedsodium chloride solution (4×250 ml.) and then dried (Na₂ SO₄).Concentration of the dried extract affords the product as an oil.

PREPARATION N 3-(3-Benzyloxyphenyl)-1-phenoxybutane

A solution of phenol (4.56 g., 48.6 mmole) in dimethylformamide (40 ml.)is added under a nitrogen atmosphere to a suspension of sodium hydride(2.32 g., 48.6 mmole) of 50% previously washed with pentane) indimethylformamide (70 ml.) at 60° C. The reaction mixture is stirred forone hour at 60°-70° C., after which a solution of3-(3-benzyloxyphenyl)butyl tosylate (18.9 g., 46 mmole) indimethylformamide (80 ml.) is added. The reaction mixture is stirred at80° C. for a half hour and is then cooled to room temperature, dilutedwith cold water (2500 ml.) and extracted with ether (4×400 ml.). Thecombined extracts are washed successively with cold 2 N hydrochloricacid (2×300 ml.) and saturated sodium chloride solution (3×300 ml.) andthen dried (Na₂ SO₄). Removal of the solvent under reduced pressureaffords the product as an oil. The oily residue is dissolved in benzeneand filtered through silica gel (100 g.). Concentration of the filtrateunder reduced pressure gives the product as an oil.

Repetition of Preparations L through N but using the 3-benzyloxyderivatives of benzaldehyde, acetophenone or propiophenone, theappropriate carbethoxy (or carbomethoxy) alkylidenetriphenylphosphorane,and the appropriate alcohol or phenol affords the following compounds.

    ______________________________________                                         ##STR13##                                                                    (alk.sub.1)    n       (alk.sub.2)                                                                              W                                           ______________________________________                                        (CH.sub.2).sub.3                                                                             1       (CH.sub.2).sub.3                                                                         H                                           (CH.sub.2).sub.3                                                                             1       (CH.sub.2).sub.5                                                                         H                                           (CH.sub.2).sub.5                                                                             1       (CH.sub.2).sub.8                                                                         H                                           (CH.sub.2).sub.6                                                                             1       (CH.sub.2).sub.7                                                                         H                                           (CH.sub.2).sub.3                                                                             1       (CH.sub.2).sub.7                                                                         H                                           (CH.sub.2).sub.3                                                                             1       (CH.sub.2).sub.10                                                                        H                                           (CH.sub.2).sub.10                                                                            1       (CH.sub.2).sub.2                                                                         H                                           C(CH.sub.3).sub.2 (CH.sub.2).sub.2                                                           1       (CH.sub.2).sub.4                                                                         H                                           (CH.sub.2).sub.4                                                                             1       CH.sub.2   C.sub.6 H.sub.5                             (CH.sub.2).sub.6                                                                             0       --         C.sub.6 H.sub.5                             (CH.sub.2).sub.13                                                                            0       --         H                                           (CH.sub.2).sub.6                                                                             0       --         H                                           (CH.sub.2).sub.6                                                                             1       CH.sub.2   4-ClC.sub.6 H.sub.4                         (CH.sub.2).sub.6                                                                             0       --         4-FC.sub.6 H.sub.4                          CH(CH.sub.3)(CH.sub.2).sub. 2                                                                0       --         C.sub.6 H.sub.5                             CH(CH.sub.3)(CH.sub.2).sub.3                                                                 0       --         C.sub.6 H.sub.5                             CH(CH.sub.3)(CH.sub.2).sub.6                                                                 0       --         H                                           (CH.sub.2).sub.3                                                                             0       --         4-pyridyl                                   (CH.sub.2).sub.3                                                                             0       --         3-pyridyl                                   (CH.sub.2).sub.3                                                                             1       CH(CH.sub.3)                                                                             2-pyridyl                                   CH(CH.sub.3)(CH.sub.2).sub.2                                                                 1       (CH.sub.2).sub.4                                                                         4-pyridyl                                   CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                          1       CH(CH.sub.3)                                                                             2-pyridyl                                   (CH.sub.2).sub.4                                                                             1       (CH.sub.2).sub.5                                                                         4-pyridyl                                   (CH.sub.2).sub.8                                                                             1       (CH.sub.2).sub.5                                                                         4-pyridyl                                   ______________________________________                                    

Bromination of the products according to the procedure of Preparation Eaffords the corresponding 2-bromo-5-[(alk₁)-O-(alk₂)_(n) -W]phenolbenzylethers.

PREPARATION O 4-(3-Hydroxyphenyl)-1-(4-pyridyl)pentane

A mixture of 3-(3-methoxyphenyl)butyl triphenylphosphonium bromide (17.5g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40ml.). The resulting mixture is then added dropwise to a slurry of 50%sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under anitrogen atmosphere at 0°-5° C. Following completion of addition, themixture is stirred for one hour at 0°-5° C. and then concentrated underreduced pressure. The concentrate is diluted with water (200 ml.) andthen acidified with 6 N HCl. The aqueous acid solution is extracted withbenzene (4×50 ml.). It is then made basic and extracted with ethylacetate (3×50 ml.). Evaporation of the combined extracts after drying(MgSO₄) affords 4-(3-methoxyphenyl)-1-(4-pyridyl)-1-pentene as an oil.

Catalytic hydrogenation of the thus-produced pentene derivative inethanol at 45 p.s.i. in the presence of Pd/C (1 g. of 10%) andconcentrated HCl (1 ml.) affords the title product.

The pentane derivative thus obtained is demethylated by heating amixture of the compound (25 mmoles) and pyridine hydrochloride (35 g.)under a nitrogen atmosphere at 210° C. for 8 hours. The hot mixture ispoured into water (40 ml.) and the resulting solution made basic with 6N sodium hydroxide. Water and pyridine are removed by distillation invacuo. Ethanol (50 ml.) is added to the residue and the inorganic saltswhich precipitate are filtered off. The filtrate is concentrated invacuo and the residue chromatographed on silica gel using as elutingagents 5% ethanol/benzene (4 liters), 10% ethanol/benzene (1 liter), 13%ethanol/benzene (1 liter) and 16% ethanol/benzene (5 liters). Theproduct is isolated by concentration of appropriate fractions of theeluate.

The 3-(3-methoxyphenyl)butyltriphenylphosphonium bromide is prepared byrefluxing a mixture of 1-bromo-3-(3-methoxyphenyl)butane (78.5 mmoles)and triphenyl phosphine (78.5 mmoles) in xylene (60 ml.) for 18 hours.The reaction mixture is then cooled to room temperature and filtered.The filter cake is washed with ether and the product dried in a vacuumdesiccator.

Repetition of this procedure but using the appropriatebromo-(3-methoxyphenyl)alkane and the appropriate aldehyde or ketoneaffords the following compounds.

    ______________________________________                                         ##STR14##                                                                    Z                      W                                                      ______________________________________                                        (CH.sub.2).sub.3       2-pyridyl                                              (CH.sub.2).sub.4       4-pyridyl                                              CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                                     3-pyridyl                                              CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                                     4-pyridyl                                              CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                                  4-pyridyl                                              (CH.sub.2).sub.10      4-pyridyl                                              ______________________________________                                    

Bromination of the above compounds according to the method ofPreparation E gives the corresponding 2-bromo-5-(Z-W)-phenols.

PREPARATION P 3-Methoxy-α-methylstyrene Oxide

To a solution of dimethylsulfoxonium methylide (69.4 mmoles) in dimethylsulfoxide (65 ml.) at room temperature is added solid3-dimethoxyacetophenone (8.33 g., 55.5 mmoles). The reaction mixture isstirred for one hour at 25° C., for one-half hour at 50° C. and is thencooled. The mixture is diluted with water (50 ml.) and added to amixture of ice water (200 ml.)--ether (250 ml.)--low boiling petroleumether (25 ml.). The organic extract is washed twice with water (250ml.), dried (MgSO₄) and evaporated to an oil which is fractionallydistilled.

PREPARATION Q 2-(3-Methoxyphenyl)-2-hydroxypropyl-2-phenylethyl Ether

A mixture of dry 2-phenylethanol (30 ml., 251 mmoles) and sodium metal(690 mg., 30 mmoles) is heated at 110° C. for 30 minutes. The resulting1 M solution of sodium 2-phenylethoxide is cooled to 60° C.,3-methoxy-α-methylstyrene oxide (1.69 g., 10.3 mmoles) added and thereaction heated 15 hours at 60° C. The reaction mixture is cooled andadded to a mixture of ether and water. The ether extract is dried overmagnesium sulfate and evaporated. Excess 2-phenylethanol is removed byvacuum distillation (b.p. ˜65° C., 0.1 mm.). The residue is purified viacolumn chromatography on silica gel 60 (300 g.) and eluted in 5 ml.fractions with 60% ether-pentane.

PREPARATION R 2-(3-Methoxyphenyl)propyl 2-Phenylethyl Ether

To a 0° C. solution of 2-(3-methoxyphenyl)-2-hydroxypropyl 2-phenylethylether (498 mg., 1.74 mmole) in pyridine (2 ml.) is added dropwisephosphorous oxychloride (0.477 μl., 5.22 mmole). The reaction is allowedto warm to 20° C. over a 1.5 hour period. It is then stirred for 1.5hours at 20° C. and then added to ether (150 ml.) and 15% sodiumcarbonate (100 ml.). The organic phase is separated and washed with 15%sodium carbonate (3×50 ml.), dried over magnesium sulfate and evaporatedto an oil. The oil is dissolved in absolute ethanol (15 ml.), 10%palladium-on-carbon (100 mg.) added and the mixture stirred under oneatmosphere of hydrogen gas. When hydrogen uptake ceases the reaction isfiltered through diatomaceous earth and the filtrate evaporated to anoil. The oil is purified via preparative layer chromatography on silicagel plates, eluted twice with 6:1 pentane:ether to yield the titlecompound.

PREPARATION S 2-(3-Hydroxyphenyl)propyl 2-Phenylethyl Ether

A mixture of 2-(3-methoxyphenyl)propyl 2-phenylethyl ether (176 mg.,0.65 mmole), pyridine (0.4 ml., 4.96 mmole) and dry pyridinehydrochloride (4 g., 34.6 mmole) is heated at 190° C. for 6 hours. Thereaction mixture is cooled and added to a mixture of water (100 ml.) andether (150 ml.). The ether extract is washed once with water (50 ml.)and, along with a second ether extract (50 ml.) of the aqueous phase, isdried over magnesium sulfate and evaporated to an oil. The oil ispurified via preparative layer chromatography on silica gel plates,eluted six times with 30% ether-pentane to yield the title product.

The following compounds are prepared from appropriate alkanols by themethods of Procedures Q and R:

    ______________________________________                                         ##STR15##                                                                    (alk.sub.2)             W                                                     ______________________________________                                        (CH.sub.2).sub.7        H                                                     (CH.sub.2).sub.6        C.sub.6 H.sub.5                                       (CH.sub.2).sub.5        H                                                     CH(CH.sub.3)CH.sub.2    H                                                     CH(CH.sub.3)(CH.sub.2).sub.5                                                                          H                                                     (CH.sub.2)              4-FC.sub.6 H.sub.4                                    (CH.sub.2).sub.2        4-pyridyl                                             (CH.sub.2).sub.2        4-ClC.sub.6 H.sub.4                                   (CH.sub.2).sub.2 CH(CH.sub.3)(CH.sub.2).sub.3                                                         H                                                     CH(CH.sub.3)CH.sub.2    H                                                     C(CH.sub.3).sub.2 CH.sub.2                                                                            H                                                     (CH.sub.2).sub.10       H                                                     CH.sub.2                C.sub.6 H.sub.5                                       ______________________________________                                    

PREPARATION T 3-Methoxy-β-methylstyrene Oxide

To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) intetrahydrofuran (one liter) is slowly added 3-methoxybenzaldehyde (1.0mole). The reaction mixture is stirred at -78° C. for 3 hours and thenallowed to warm to room temperature. It is then added to ether-water andthe ether phase separated. The ether phase is washed with water, dried(MgSO₄) and evaporated. Fractional distillation of the residue gives thetitle product.

PREPARATION U 3-(3-Hydroxyphenyl)-2-propylbutyl Ether

To a solution of sodium butoxide in butanol (0.5 liters of 1 M) is added3-methoxy-β-methylstyrene oxide (6.33 mole). The mixture is heated for18 hours at 70° C. and is then cooled and added to a mixture ofether-water. The ether solution is separated, dried (MgSO₄) andevaporated to give the crude product2-(3-methoxyphenyl)-3-hydroxy-2-propylbutyl ether. It is purified bycolumn chromatography on silica gel with ether-pentane elution.

By means of the procedure of Preparation R the title product isproduced.

Similarly, the following are prepared from appropriate alcohols:

    ______________________________________                                         ##STR16##                                                                    (alk.sub.2)            W                                                      ______________________________________                                        (CH.sub.2).sub.2       H                                                      (CH.sub.2).sub.7       H                                                      (CH.sub.2).sub.3       C.sub.6 H.sub.5                                        (CH.sub.2).sub.2       4-FC.sub.6 H.sub.4                                     (CH.sub.2).sub.2       4-pyridyl                                              CH(CH.sub.3)(CH.sub.2).sub.2                                                                         H                                                      CH(C.sub.2 H.sub.5)(CH.sub.2).sub.3                                                                  H                                                      CH(CH.sub.3)CH.sub.2   C.sub.6 H.sub.5                                        CH.sub.2               H                                                      (CH.sub.2).sub.2       4-ClC.sub.6 H.sub.4                                    ______________________________________                                    

PREPARATION V 1-Bromo-3-(3-methoxyphenyl)butane

A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30ml.) is added to a solution of 3-(3-methoxyphenyl)-1-butanol (30.0 g.,0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reactionmixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed toroom temperature and stirred for an additional 30 minutes. The mixtureis poured over ice (200 g.) and the resulting mixture extracted withether (3×50 ml.). The combined extracts are washed with 5% sodiumhydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50ml.) and dried (Na₂ SO₄). Removal of the ether and vacuum distillationof the residue affords the title product.

The following compounds are prepared from 3-methoxybenzaldehyde,3-methoxyacetophenone and 3-methoxypropiophenone and the appropriatecarbethoxyalkylidene triphenylphosphorane by the procedures ofPreparations L, M and the above procedure.

    ______________________________________                                         ##STR17##                                                                                  Z                                                               ______________________________________                                                   (CH.sub.2).sub.3                                                              (CH.sub.2).sub.4                                                              CH(C.sub.2 H.sub.5)CH.sub.2                                                   CH(CH.sub.3)CH.sub.2                                                          CH(CH.sub.3)(CH.sub.2).sub.3                                       ______________________________________                                    

PREPARATION W β-(2-Pyridyl)vinyl phenyl ketone

A slurry of sodium hydride (50%, 2.4 g., 0.05 mole) in 100 ml. of dry1,2-dimethoxyethane is cooled to 20° C. and diethyl phenacylphosphonate(11.4 g., 0.05 mole) added dropwise with stirring. The mixture isstirred at room temperature until gas evolution ceases. Then,2-pyridinecarboxaldehyde (5.36 g., 0.05 mole) is added dropwise at 20°C. The mixture is stirred for one hour at 20°-25° C. and then refluxedfor one hour. It is then cooled, a large excess of water added and theproduct extracted with ether. The extract is dried (MgSO₄) andevaporated to give the product.

By means of this procedure, the following α,β-unsaturated ketones andare prepared from appropriate dialkyl (dimethyl or diethyl) acylphosphonates [(CH₃ O)₂ P(O)--CH₂ COR₄ ] and appropriate aldehydes orketones (R₂ R₃ CO).

    ______________________________________                                        R.sub.4COCHCR.sub.2 R.sub.3                                                   R.sub.2         R.sub.3    R.sub.4                                            ______________________________________                                        H               H          2-pyridyl                                          H               H          3-pyridyl                                          H               H          4-pyridyl                                          H               H          CH.sub.2 .sub.6 H.sub.5                            H               H          (CH.sub.2).sub.4 C.sub.6 H.sub.5                   CH.sub.3        H          4-pyridyl                                          n-C.sub.4 H.sub.9                                                                             H          4-pyridyl                                          n-C.sub.3 H.sub.7                                                                             H          4-pyridyl                                          n-C.sub.6 H.sub.13                                                                            H          4-pyridyl                                          CH.sub.3        H          2-pyridyl                                          i-C.sub.6 H.sub.13                                                                            H          2-pyridyl                                          CH.sub.3        H          3-pyridyl                                          n-C.sub.5 H.sub.11                                                                            H          3-pyridyl                                          C.sub.6 H.sub.5 H          2-pyridyl                                          C.sub.6 H.sub.5 H          3-pyridyl                                          C.sub.6 H.sub.5 H          4-pyridyl                                          CH.sub.2 C.sub.6 H.sub.5                                                                      H          4-pyridyl                                          (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                              H          4-pyridyl                                          CH.sub.2 C.sub.6 H.sub.5                                                                      H          3-pyridyl                                          CH.sub.2 C.sub.6 H.sub.5                                                                      H          2-pyridyl                                          (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                              H          2-pyridyl                                          4-pyridyl       H          4-pyridyl                                          4-pyridyl       H          2-pyridyl                                          2-pyridyl       H          2-pyridyl                                          4-pyridyl       H          3-pyridyl                                          4-pyridyl       H          H                                                  2-pyridyl       H          H                                                  3-pyridyl       H          H                                                  C.sub.6 H.sub.5 H          CH.sub.2 C.sub.6 H.sub.5                           4-pyridyl       H          C.sub.6 H.sub.5                                    3-pyridyl       H          C.sub.6 H.sub.5                                    2-pyridyl       H          C.sub.6 H.sub.5                                    4-pyridyl       H          CH.sub.3                                           4-pyridyl       H          n-C.sub.3 H.sub.7                                  4-pyridyl       H          i-C.sub.6 H.sub.13                                 2-pyridyl       H          CH.sub.3                                           2-pyridyl       H          n-C.sub.4 H.sub.9                                  3-pyridyl       H          n-C.sub.3 H.sub.7                                  3-pyridyl       H          CH.sub.2 C.sub.6 H.sub.5                           4-pyridyl       H          CH.sub.2 C.sub.6 H.sub.5                           4-pyridyl       H          (CH.sub.2).sub.4 C.sub.6 H.sub.5                   2-pyridyl       H          (CH.sub.2).sub.3 C.sub.6 H.sub.5                   H               H          C.sub.6 H.sub.5                                    CH.sub.2 C.sub.6 H.sub.5                                                                      H          CH.sub.2 C.sub.6 H.sub.5                           CH.sub.2 C.sub.6 H.sub.5                                                                      H          (CH.sub.2).sub.3 C.sub.6 H.sub.5                   (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                              H          CH.sub.2 C.sub.6 H.sub.5                           CH.sub.2 C.sub.6 H.sub.5                                                                      H          C.sub.6 H.sub.5                                    (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                              H          C.sub.6 H.sub.5                                    CH.sub.2 C.sub.6 H.sub.5                                                                      H          CH.sub.3                                           (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                              H          CH.sub.3                                           CH.sub.2 C.sub.6 H.sub.5                                                                      H          n-C.sub.6 H.sub.13                                 CH.sub.3        H          CH.sub.2 C.sub.6 H.sub.5                           n-C.sub.4 H.sub.9                                                                             H          CH.sub.2 C.sub.6 H.sub.5                           CH.sub.3        H          (CH.sub.2).sub.4 C.sub.6 H.sub.5                   n-C.sub.6 H.sub.13                                                                            H          (CH.sub.2).sub.4 C.sub.6 H.sub.5                   n-C.sub.5 H.sub.11                                                                            H          n-C.sub.6 H.sub.13                                 i-C.sub.6 H.sub.13                                                                            H          CH.sub.3                                           n-C.sub.6 H.sub.13                                                                            H          n-C.sub.6 H.sub.13                                 CH.sub.3        CH.sub.3   CH.sub.3                                           n-C.sub.4 H.sub.9                                                                             CH.sub.3   CH.sub.3                                           CH.sub.3        CH.sub.3   n-C.sub.4 H.sub.9                                  CH.sub.3        CH.sub.3   n-C.sub.6 H.sub.13                                 C.sub.6 H.sub.5 CH.sub.3   CH.sub.3                                           t-C.sub.4 H.sub.9                                                                             CH.sub.3   CH.sub.3                                           CH.sub.3        CH.sub.3   C.sub.6 H.sub.5                                    CH.sub.3        CH.sub.3   CH.sub.2 C.sub.6 H.sub.5                           C.sub.2 H.sub.5 CH.sub.3   CH.sub.2 C.sub.6 H.sub.5                           CH.sub.3        CH.sub.3   (CH.sub.2).sub.3 C.sub.6 H.sub.5                   n-C.sub.6 H.sub.13                                                                            CH.sub.3   CH.sub.2 C.sub.6 H.sub.5                           CH.sub.3        CH.sub.3   4-pyridyl                                          n-C.sub.4 H.sub.9                                                                             CH.sub.3   4-pyridyl                                          i-C.sub.6 H.sub.13                                                                            CH.sub.3   2-pyridyl                                          CH.sub.3        CH.sub.3   2-pyridyl                                          C.sub.6 H.sub.5 CH.sub.3   4-pyridyl                                          4-pyridyl       CH.sub.3   C.sub.6 H.sub.5                                    4-pyridyl       CH.sub.3   4-pyridyl                                          CH.sub.2 C.sub.6 H.sub.5                                                                      CH.sub.3   2-pyridyl                                          C.sub.6 H.sub. 5                                                                              CH.sub.3   n-C.sub.5 H.sub.11                                 CH.sub.3        CH.sub.3   (CH.sub.2).sub.3 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 CH.sub.3   CH.sub.2 C.sub.6 H.sub.5                           i-C.sub.3 H.sub.7                                                                             H          CH.sub.3                                           i-C.sub.3 H.sub.7                                                                             H          C.sub.2 H.sub.5                                    ______________________________________                                    

What is claimed is:
 1. A compound having the formula: ##STR18## whereinR is selected from the group consisting of hydrogen and alkanoyl havingfrom one to five carbon atoms;R₁ is selected from the group consistingof hydrogen, benzyl, alkanoyl having from one to five carbon atoms,P(O)(OH)₂ and mono- and disodium and potassium salts thereof, --CO(CH₂)₂COOH and sodium and potassium salts thereof, and --CO--(CH₂)_(p) --NR₅R₆ wherein p is 0 or an integer from 1 to 4; each of R₅ and R₆ whentaken individually is selected from the group consisting of hydrogen andalkyl having from one to four carbon atoms; R₅ and R₆ when takentogether with the nitrogen to which they are attached form a 5- or6-membered heterocyclic ring selected from the group consisting ofpiperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazinohaving from one to four carbon atoms in the alkyl group; each of R₂ andR₄ is selected from the group consisting of hydrogen, alkyl having fromone to six carbon atoms, phenyl, pyridyl and phenylalkyl having from oneto four carbon atoms in the alkyl moiety; R₃ is selected from the groupconsisting of hydrogen and methyl; Z is selected from the groupconsisting of (a) alkylene having from one to thirteen carbon atoms; (b)--(alk₁)_(m) --O--(alk₂)_(n) -- wherein each of (alk₁) and (alk₂) isalkylene having from one to thirteen carbon atoms, with the proviso thatthe summation of carbon atoms in (alk₁) plus (alk₂) is not greater thanthirteen; each of m and n is 0 or 1; and W is selected from the groupconsisting of hydrogen, pyridyl, ##STR19## wherein W₁ is selected fromthe group consisting of hydrogen, fluoro and chloro; and thepharmaceutically acceptable acid addition salts of those compoundswherein R₁ is --CO--(CH₂)_(p) --NR₅ R₆ and/or R₂, R₄ or W is pyridyl. 2.A compound according to claim 1 wherein each of R and R₁ is hydrogen andZ is alkylene.
 3. A compound according to claim 2 wherein Z is alkylenehaving from 5 to 9 carbon atoms.
 4. A compound according to claim 3wherein Z is C(CH₃)₂ (CH₂)₆ and W is hydrogen.
 5. A compound accordingto claim 4 wherein R₃ is hydrogen and each of R₂ and R₄ is alkyl.
 6. Thecompound according to claim 5 wherein R₄ is ethyl and R₂ is isopropyl.7. A compound according to claim 3 wherein W is ##STR20##
 8. A compoundaccording to claim 7 wherein Z is CH(CH₃)(CH₂)₃, W is ##STR21## each ofR₂ and R₄ is alkyl and R₃ is methyl.
 9. The compound according to claim8 wherein each of R₂ and R₄ is ethyl.
 10. A compound according to claim1 wherein each of R and R₁ is hydrogen and Z is --(alk₁)_(m)--O--(alk₂)_(n) --.
 11. A compound according to claim 10 wherein Z is--O--(alk₂)-- and W is ##STR22##
 12. A compound according to claim 11wherein Z is --O--CH(CH₃)(CH₂)₃ --, W is ##STR23## and each of R₂ and R₄is alkyl.
 13. The compound according to claim 12 wherein R₂ is i--C₃ H₇and R₄ is ethyl.
 14. A compound according to claim 5 wherein R₃ ishydrogen and each of R₂ and R₄ is methyl.